title: Identifying reaction modules in metabolic pathways: bioinformatic deduction and experimental validation of a new putative route in purine catabolism.
abstract: BACKGROUND
  Enzymes belonging to mechanistically diverse superfamilies often display similar catalytic mechanisms. We previously observed such an association in the case of the cyclic amidohydrolase superfamily whose members play a role in related steps of purine and pyrimidine metabolic pathways. To establish a possible link between enzyme homology and chemical similarity, we investigated further the neighbouring steps in the respective pathways.
  
  
  RESULTS
  We identified that successive reactions of the purine and pyrimidine pathways display similar chemistry. These mechanistically-related reactions are often catalyzed by homologous enzymes. Detection of series of similar catalysis made by succeeding enzyme families suggested some modularity in the architecture of the central metabolism. Accordingly, we introduce the concept of a reaction module to define at least two successive steps catalyzed by homologous enzymes in pathways alignable by similar chemical reactions. Applying such a concept allowed us to propose new function for misannotated paralogues. In particular, we discovered a putative ureidoglycine carbamoyltransferase (UGTCase) activity. Finally, we present experimental data supporting the conclusion that this UGTCase is likely to be involved in a new route in purine catabolism.
  
  
  CONCLUSIONS
  Using the reaction module concept should be of great value. It will help us to trace how the primordial promiscuous enzymes were assembled progressively in functional modules, as the present pathways diverged from ancestral pathways to give birth to the present-day mechanistically diversified superfamilies. In addition, the concept allows the determination of the actual function of misannotated proteins.
authors.affiliation: Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris Sud, Bâtiment 400, 91405, Orsay Cedex, France. bernard.labedan@igmors.u-psud.fr.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Barba
authors.forename: Raphaël
authors.initials: R
authors.lastname: Dutoit
authors.forename: Christianne
authors.initials: C
authors.lastname: Legrain
authors.forename: Bernard
authors.initials: B
authors.lastname: Labedan
mesh_terms: D019878:Carboxyl and Carbamoyl Transferases / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D000090722:Dihydroorotate Dehydrogenase; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D010802:Phylogeny; D011687:Purines / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D011687:Purines; C549215:ureidoglycine; D014508:Urea; D044925:Oxidoreductases Acting on CH-CH Group Donors; D042943:Dihydrouracil Dehydrogenase (NADP); D019878:Carboxyl and Carbamoyl Transferases; D005998:Glycine; C030985:purine